학술논문
Design of cell-type-specific hyperstable IL-4 mimetics via modular de novo scaffolds
Document Type
Original Paper
Author
Yang, Huilin; Ulge, Umut Y.; Quijano-Rubio, Alfredo; Bernstein, Zachary J.; Maestas, David R.; Chun, Jung-Ho; Wang, Wentao; Lin, Jian-Xin; Jude, Kevin M.; Singh, Srujan; Orcutt-Jahns, Brian T.; Li, Peng; Mou, Jody; Chung, Liam; Kuo, Yun-Huai; Ali, Yasmin H.; Meyer, Aaron S.; Grayson, Warren L.; Heller, Nicola M.; Garcia, K. Christopher; Leonard, Warren J.; Silva, Daniel-Adriano; Elisseeff, Jennifer H.; Baker, David; Spangler, Jamie B.
Source
Nature Chemical Biology. 19(9):1127-1137
Subject
Language
English
ISSN
1552-4450
1552-4469
1552-4469
Abstract
The interleukin-4 (IL-4) cytokine plays a critical role in modulating immune homeostasis. Although there is great interest in harnessing this cytokine as a therapeutic in natural or engineered formats, the clinical potential of native IL-4 is limited by its instability and pleiotropic actions. Here, we design IL-4 cytokine mimetics (denoted Neo-4) based on a de novo engineered IL-2 mimetic scaffold and demonstrate that these cytokines can recapitulate physiological functions of IL-4 in cellular and animal models. In contrast with natural IL-4, Neo-4 is hyperstable and signals exclusively through the type I IL-4 receptor complex, providing previously inaccessible insights into differential IL-4 signaling through type I versus type II receptors. Because of their hyperstability, our computationally designed mimetics can directly incorporate into sophisticated biomaterials that require heat processing, such as three-dimensional-printed scaffolds. Neo-4 should be broadly useful for interrogating IL-4 biology, and the design workflow will inform targeted cytokine therapeutic development.
De novo designed interleukin-4 mimetics were engineered that induce biased signaling activation and exhibit high thermal stability. These mimetics offer insight into cytokine signaling and can be directly incorporated into 3D-printed biomaterials
De novo designed interleukin-4 mimetics were engineered that induce biased signaling activation and exhibit high thermal stability. These mimetics offer insight into cytokine signaling and can be directly incorporated into 3D-printed biomaterials